Article: Valaciclovir

Valaciclovir
Systematic (IUPAC) name
2-[(2-amino-6-oxo-3,9-dihydropurin-9-yl)methoxy] ethyl-2-amino-3-methyl-butanoate
Identifiers
CAS number	124832-27-5
ATC code	J05AB11
PubChem	60773
DrugBank	APRD00697
Chemical data
Formula	C13H20N6O4
Mol. weight	324.336 g/mol
Pharmacokinetic data
Bioavailability	55%
Protein binding	13–18%
Metabolism	Hepatic (to aciclovir)
Half life	<30 minutes (valaciclovir); 2.5-3.6 hours (aciclovir)
Excretion	Renal 40–50% (aciclovir), faecal 47% (aciclovir)
Therapeutic considerations
Pregnancy cat.	B3 (Au), B (U.S.)
Legal status	S4 (Au), POM (UK), ℞-only (U.S.)
Routes	Oral

Valaciclovir (INN) or valacyclovir (USAN) is an antiviral drug used in the management of herpes simplex and herpes zoster (shingles). It is a prodrug, being converted in vivo to aciclovir. It is marketed by GlaxoSmithKline under the trade name Valtrex.

Pharmacology

Mechanism of action

Valaciclovir is a prodrug that is converted by esterases to the active drug aciclovir via hepatic first-pass metabolism. Aciclovir is selectively converted into a monophosphate form by viral thymidine kinase, which is far more effective (3000 times) in phosphorylation than cellular thymidine kinase. Subsequently, the monophosphate form is further phosphorylated into the active triphosphate form, aciclo-GTP, by cellular kinases. Aciclo-GTP is a very potent inhibitor of viral DNA polymerase; it has approximately 100 times higher affinity to viral than cellular polymerase. Its monophosphate form also incorporates into the viral DNA, resulting in chain termination. It has also been shown that the viral enzymes cannot remove aciclo-GMP from the chain, which results in inhibition of further activity of DNA polymerase. Aciclo-GTP is fairly rapidly metabolised within the cell, possibly by cellular phosphatases.

Microbiology

Aciclovir, the active metabolite of valaciclovir, is active against most species in the herpesvirus family. In descending order of activity:^[1]

• Herpes simplex virus type I (HSV-1)
• Herpes simplex virus type II (HSV-2)
• Varicella zoster virus (VZV)
• Epstein-Barr virus (EBV)
• Cytomegalovirus (CMV)

Activity is predominately active against HSV, and to a lesser extent VZV. It is only of limited efficacy against EBV and CMV. It is inactive against latent viruses in nerve ganglia.

To date, resistance to valaciclovir has not been clinically significant. Mechanisms of resistance in HSV include deficient viral thymidine kinase; and mutations to viral thymidine kinase and/or DNA polymerase, altering substrate sensitivity.^[2]

Clinical use

Indications

Valaciclovir is indicated for the treatment of HSV and VZV infections, including:^[3]

• Genital herpes simplex (treatment and prophylaxis)
• Reduction of HSV transmission from people with recurrent infection to uninfected individuals
• Herpes zoster (shingles)
• Prevention of CMV disease following organ transplantation

Adverse effects

Common adverse drug reactions (≥1% of patients) associated with valaciclovir therapy are the same as for aciclovir, its active metabolite, and include: nausea, vomiting, diarrhoea and/or headache. Infrequent adverse effects (0.1–1% of patients) include: agitation, vertigo, confusion, dizziness, oedema, arthralgia, sore throat, constipation, abdominal pain, rash, weakness and/or renal impairment. Rare adverse effects (<0.1% of patients) include: coma, seizures, neutropenia, leucopenia, tremor, ataxia, encephalopathy, psychotic symptoms, crystalluria, anorexia, fatigue, hepatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis and/or anaphylaxis.^[3]